1. Field
This invention relates to chemical compositions generally, especially to stable solid pharmaceutical preparations containing the water soluble acid addition salt of a poorly soluble basic compound.
2. State of the Art
Methods for making tablets and other solid or dry pharmaceutical preparations are well-known. For example in Chase, et al, Remington's Pharmaceutical Sciences. pp. 1553-1576 (16th ed. 1980, Mack Publ. Co. of Easton, Pa., U.S.A.), methods of making tablets, capsules and pills and their respective components are described.
Two methods of making tablets are the "wet-granulation" and "dry-granulation" methods. The dry granulation method is especially suitable for medicinal compounds which are sensitive to moisture or are unable to withstand elevated drying temperatures associated with the wet-granulation methods.
Even with the use of these granulation methods however, the tableting of certain compounds (e.g. the water soluble acid addition salts of poorly soluble basic drugs) is less than ideal. Granulation processes using these compounds are not very "rugged", i.e. the processes have relatively strict tolerances making the granulation process extremely sensitive to changes in process variables (e.g. temperature and moisture changes). A process which is not very rugged has relatively strict operating tolerances which make the process sensitive to changes in processing variables. This is especially disadvantageous with regard to high temperature granulation processes which involve high temperatures and high humidities.
Even after tablets or other dry dosage pharmaceutical preparations are made containing the water soluble acid addition salts of poorly soluble basic drugs, the resulting preparations are generally not very stable. They discolour and/or degrade under certain conditions. For example, they may discolour or degrade upon exposure to light, relatively high humidity, or elevated temperatures. Color changes and degradation are tokens of instability. These tokens of instability may occur rather rapidly, sometimes within months, forcing a pharmacist or wholesaler storing the tablets to restock the product frequently.
The compound sodium pyrophosphate (Na.sub.4 P.sub.2 O.sub.7) has been described as stabilizing certain calcium phosphate compounds. For example in U.S. Pat. No. 2,287,699 to Moss et al, alkali metal pyrophosphates (e.g. Na.sub.4 P.sub.2 O.sub.7) are used to prepare a stabilized form of dicalcium phosphate (e.g. CaHPO.sub.4.2H.sub.2 O). In U.S. Pat. No. 3,012,852 to Nelson et al, a process for producing "internally stabilized" dicalcium phosphate dihydrate using pyrophosphate ions is also disclosed.
Certain magnesium compounds are also known to stabilize calcium phosphate compounds. For example in U.S. Pat. No. 2,018,410 to McDonald et al, trimagnesium phosphate, magnesium sulfate, magnesium stearate, and dimagnesium phosphate are all described as stabilizing hydrated dicalcium phosphate compounds substantially free from monocalcium phosphate for use in dentifrice preparations. In GB 1,548,465 to Hoechst Aktiengesellschaft, dimagnesium phosphate trihydrate is used to stabilize dicalcium phosphate dihydrate. In U.S. Pat. No. 3,411,873 to Harnisch et al, a process for stabilizing dicalcium phosphate dihydrate by means of a magnesium phosphate is disclosed.
In German patent application DE 2,741,513 to J. H. Benckiser GmbH, a procedure is described for stabilizing calcium hydrogen phosphate dihydrate against hydrolysis using a diphosphonic acid or its water-soluble salt.
In European Patent 054,333 to Stauffer Chemical Co., fine particles of a calcium phosphate (e.g. calcium pyrophosphate) are compacted under pressure to form a sheet. The sheet may then be comminuted to give a granular material. This granular material may then be used as an excipient in pharmaceutical tablets or wafers.
U.S. Pat. No. 4,743,450 to Harris et al discloses pharmaceutical compositions containing a drug (i.e. an ACE inhibitor), an alkaline stabilizer, and a saccharide. Harris et al prefers water insoluble stabilizers such as magnesium carbonate, calcium carbonate, and magnesium silicate, which have not always proved adequate in trying to stabilize a high temperature, high humidity granulation process. Harris et al also specifically requires a saccharide component in the described compositions, which unnecessarily adds to the costs of such compositions. Harris et al furthermore does not disclose any methods of increasing the ruggedness of a granulation procedure, nor does the reference disclose rugged granulation procedures utilizing temperatures greater than 45.degree. C. It is now found that when the drying temperature exceeds 45.degree. C., such procedures become less rugged. The same criticality is found with regard to granulation temperatures.
European patent application 380,021 to Abbott Laboratories discloses that buffers may be used to obtain complete solubilization of certain drugs, and that these buffers can increase the thermal stability of a drug formulation during the drying step of the granulation process. It also discloses solid dosage forms having increased stability which may contain estropipate, a tromethamine buffer, and an additional alkaline buffering agent, such as dibasic sodium phosphate. The dosage forms may also contain an excipient, such as dibasic calcium phosphate.
To date no one has been able to economically increase the ruggedness of a high temperature mixing step of granulation procedures involving certain unstable chemical compounds (e.g. the water soluble acid addition salt of a poorly soluble basic compound).